Motor Recovery after Chronic Spinal Cord Transection in Rats: A Proof-of-Concept Study Evaluating a Combined Strategy

Author(s): Antonio Ibarra*, Erika Mendieta-Arbesú, Paola Suarez-Meade, Elisa García-Vences, Susana Martiñón, Roxana Rodriguez-Barrera, Joel Lomelí, Adrian Flores-Romero, Raúl Silva-García, Vinnitsa Buzoianu-Anguiano, Cesar V. Borlongan, Tamara D. Frydman.

Journal Name: CNS & Neurological Disorders - Drug Targets

Volume 18 , Issue 1 , 2019

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Graphical Abstract:


Background: The chronic phase of Spinal Cord (SC) injury is characterized by the presence of a hostile microenvironment that causes low activity and a progressive decline in neurological function; this phase is non-compatible with regeneration. Several treatment strategies have been investigated in chronic SC injury with no satisfactory results. OBJECTIVE- In this proof-of-concept study, we designed a combination therapy (Comb Tx) consisting of surgical glial scar removal plus scar inhibition, accompanied with implantation of mesenchymal stem cells (MSC), and immunization with neural-derived peptides (INDP).

Methods: This study was divided into three subsets, all in which Sprague Dawley rats were subjected to a complete SC transection. Sixty days after injury, animals were randomly allocated into two groups for therapeutic intervention: control group and animals receiving the Comb-Tx. Sixty-three days after treatment we carried out experiments analyzing motor recovery, presence of somatosensory evoked potentials, neural regeneration-related genes, and histological evaluation of serotoninergic fibers.

Results: Comb-Tx induced a significant locomotor and electrophysiological recovery. An increase in the expression of regeneration-associated genes and the percentage of 5-HT+ fibers was noted at the caudal stump of the SC of animals receiving the Comb-Tx. There was a significant correlation of locomotor recovery with positive electrophysiological activity, expression of GAP43, and percentage of 5-HT+ fibers.

Conclusion: Comb-Tx promotes motor and electrophysiological recovery in the chronic phase of SC injury subsequent to a complete transection. Likewise, it is capable of inducing the permissive microenvironment to promote axonal regeneration.

Keywords: Evoked potentials, Fibrin glue, GAP43, mesenchymal stem cells, neural-derived peptides, protective autoimmunity, neural regeneration, scar removal, serotonin.

Hesp ZC, Yoseph RY, Suzuki R, et al. Proliferating NG2-Cell-Dependent Angiogenesis and Scar Formation Alter Axon Growth and Functional Recovery After Spinal Cord Injury in Mice. J Neurosci 2018; 38(6): 1366-82.
Andrews EM, Richards RJ, Yin FQ, Viapiano MS, Jakeman LB. Alterations in chondroitin sulfate proteoglycan expression occur both at and far from the site of spinal contusion injury. Exp Neurol 2012; 235(1): 174-87.
Cregg JM, DePaul MA, Filous AR, Lang BT, Tran A, Silver J. Functional regeneration beyond the glial scar. Exp Neurol 2014; 253: 197-207.
Storer PD, Houle JD. BetaII-tubulin and GAP 43 mRNA expression in chronically injured neurons of the red nucleus after a second spinal cord injury. Exp Neurol 2003; 183(2): 537-47.
Rodriguez-Barrera R, Flores-Romero A, Fernandez-Presas AM, et al. Immunization with neural derived peptides plus scar removal induces a permissive microenvironment, and improves locomotor recovery after chronic spinal cord injury. BMC Neurosci 2017; 18(1): 7.
Cioato SG, Medeiros LF, Marques Filho PR, et al. Long-Lasting Effect of Transcranial Direct Current Stimulation in the Reversal of Hyperalgesia and Cytokine Alterations Induced by the Neuropathic Pain Model. Brain Stimul 2016; 9(2): 209-17.
El-Kheir WA, Gabr H, Awad MR, et al. Autologous bone marrow-derived cell therapy combined with physical therapy induces functional improvement in chronic spinal cord injury patients. Cell Transplant 2014; 23(6): 729-45.
Holly LT, Blaskiewicz D, Wu A, Feng C, Ying Z, Gomez-Pinilla F. Dietary therapy to promote neuroprotection in chronic spinal cord injury. J Neurosurg Spine 2012; 17(2): 134-40.
Huang H, Xi H, Chen L, Zhang F, Liu Y. Long-term outcome of olfactory ensheathing cell therapy for patients with complete chronic spinal cord injury. Cell Transplant 2012; 21(1): 23-31.
Walker JB, Harris M. GM-1 ganglioside administration combined with physical therapy restores ambulation in humans with chronic spinal cord injury. Neurosci Lett 1993; 161(2): 174-8.
Rodriguez-Barrera R, Fernandez-Presas AM, Garcia E, et al. Immunization with a neural-derived peptide protects the spinal cord from apoptosis after traumatic injury. BioMed Res Int 2013.
Ibarra A, Garcia E, Flores N, et al. Immunization with neural-derived antigens inhibits lipid peroxidation after spinal cord injury. Neurosci Lett 2010; 476(2): 62-5.
Garcia E, Silva-Garcia R, Flores-Romero A, Blancas-Espinoza L, Rodriguez-Barrera R, Ibarra A. The Severity of Spinal Cord Injury Determines the Inflammatory Gene Expression Pattern after Immunization with Neural-Derived Peptides. J Mol Neurosci 2018. 65(2): 190-5.
Garcia E, Silva-Garcia R, Mestre H, et al. Immunization with A91 peptide or copolymer-1 reduces the production of nitric oxide and inducible nitric oxide synthase gene expression after spinal cord injury. J Neurosci Res 2012; 90(3): 656-63.
Martinon S, Garcia-Vences E, Toscano-Tejeida D, et al. Long-term production of BDNF and NT-3 induced by A91-immunization after spinal cord injury. BMC Neurosci 2016; 17(1): 42.
Kim M, Kim KH, Song SU, et al. Transplantation of human bone marrow-derived clonal mesenchymal stem cells reduces fibrotic scar formation in a rat spinal cord injury model. J Tissue Eng Regen Med 2018; 12(2): 1034-45.
Wang H, Xiong B, Chen H, et al. Effect of bone marrow mesenchymal stem cells on lipopolysacharide-induced secretion of inflammatory cytokines in rat macrophages in vitro. Nan Fang Yi Ke Da Xue Xue Bao 2014; 34(9): 1259-64.
Cizkova D, Cubinkova V, Smolek T, et al. Localized Intrathecal Delivery of Mesenchymal Stromal Cells Conditioned Medium Improves Functional Recovery in a Rat Model of Spinal Cord Injury. Int J Mol Sci 2018; 19(3) E870.
Xiao Z, Tang F, Zhao Y, et al. Significant Improvement of Acute Complete Spinal Cord Injury Patients Diagnosed by a Combined Criteria Implanted with NeuroRegen Scaffolds and Mesenchymal Stem Cells. Cell Transplant 2018. 27(6): 907-15
Lin L, Lin H, Bai S, Zheng L, Zhang X. Bone marrow mesenchymal stem cells (BMSCs) improved functional recovery of spinal cord injury partly by promoting axonal regeneration. Neurochem Int 2018; 115: 80-4.
Li Y, Zhao Q. The effects of fibrin glue on acute complete transection spinal cord injury. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2008; 22(7): 828-31.
Fang H, Peng S, Chen A, Li F, Ren K, Hu N. Biocompatibility studies on fibrin glue cultured with bone marrow mesenchymal stem cells in vitro. J Huazhong Univ Sci Technolog Med Sci 2004; 24(3): 272-4.
Wu JC, Huang WC, Chen YC, et al. Acidic fibroblast growth factor for repair of human spinal cord injury: a clinical trial. J Neurosurg Spine 2011; 15(3): 216-27.
Martinon S, Garcia E, Flores N, et al. Vaccination with a neural-derived peptide plus administration of glutathione improves the performance of paraplegic rats. Eur J Neurosci 2007; 26(2): 403-12.
Fitzpatrick MA, Suda KJ, Safdar N, et al. Changes in bacterial epidemiology and antibiotic resistance among veterans with spinal cord injury/disorder over the past 9 years. J Spinal Cord Med 2018; 41(2): 199-207.
Biering-Sorensen F, Biering-Sorensen T, Liu N, Malmqvist L, Wecht JM, Krassioukov A. Alterations in cardiac autonomic control in spinal cord injury. Auton Neurosci 2018; 209: 4-18.
Ziv Y, Avidan H, Pluchino S, Martino G, Schwartz M. Synergy between immune cells and adult neural stem/progenitor cells promotes functional recovery from spinal cord injury. Proc Natl Acad Sci USA 2006; 103(35): 13174-9.
Wang Y, Kong QJ, Sun JC, et al. Lentivirus-mediated silencing of the CTGF gene suppresses the formation of glial scar tissue in a rat model of spinal cord injury. Spine J 2018; 18(1): 164-72.
Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 2010; 133(2): 433-47.
Karimi-Abdolrezaee S, Eftekharpour E, Fehlings MG. Temporal and spatial patterns of Kv1.1 and Kv1.2 protein and gene expression in spinal cord white matter after acute and chronic spinal cord injury in rats: implications for axonal pathophysiology after neurotrauma. Eur J Neurosci 2004; 19(3): 577-89.
Kasahara K, Nakagawa T, Kubota T. Neuronal loss and expression of neurotrophic factors in a model of rat chronic compressive spinal cord injury. Spine 2006; 31(18): 2059-66.
Wang L, Wang Q, Zhang XM. Progress on bone marrow mesenchymal stem cells transplantation for spinal cord injury. Zhongguo Gu Shang 2014; 27(5): 437-40.
Lees JR. Interferon gamma in autoimmunity: A complicated player on a complex stage. Cytokine 2015; 74(1): 18-26.
Keefe KM, Sheikh IS, Smith GM. Targeting Neurotrophins to Specific Populations of Neurons: NGF, BDNF, and NT-3 and Their Relevance for Treatment of Spinal Cord Injury. Int J Mol Sci 2017; 18(3) E548.
Tang F, Guo S, Liao H, et al. Resveratrol Enhances Neurite Outgrowth and Synaptogenesis Via Sonic Hedgehog Signaling Following Oxygen-Glucose Deprivation/Reoxygenation Injury. Cell Physiol Biochem 2017; 43(2): 852-69.
Liu Z, Sun Y, Qiao Q, et al. Sesamol ameliorates high-fat and high-fructose induced cognitive defects via improving insulin signaling disruption in the central nervous system. Food Funct 2017; 8(2): 710-9.
Sugino T, Maruyama M, Tanno M, Kuno A, Houkin K, Horio Y. Protein deacetylase SIRT1 in the cytoplasm promotes nerve growth factor-induced neurite outgrowth in PC12 cells. FEBS Lett 2010; 584(13): 2821-6.
Huang R, Zhao J, Ju L, Wen Y, Xu Q. The influence of GAP-43 on orientation of cell division through G proteins Int J Dev Neurosci 2015; 47(Pt B): 333-9.
Yang Z, Duan H, Mo L, Qiao H, Li X. The effect of the dosage of NT-3/chitosan carriers on the proliferation and differentiation of neural stem cells. Biomaterials 2010; 31(18): 4846-54.
Binder DK, Scharfman HE. Brain-derived neurotrophic factor. Growth Factors 2004; 22(3): 123-31.
Gupta SK, Mishra R, Kusum S, et al. GAP-43 is essential for the neurotrophic effects of BDNF and positive AMPA receptor modulator S18986. Cell Death Differ 2009; 16(4): 624-37.
Maisonpierre PC, Belluscio L, Squinto S, Furth ME, Lindsay RM, Yancopoulos GD. Neurotrophin-3: a neurotrophic factor related to NGF and BDNF. Science 1990; 247(4949 Pt 1): 1446-51.
Liu W, Wang Y, Gong F, et al. Exosomes derived from bone mesenchymal stem cells repair traumatic spinal cord injury via suppressing the activation of A1 neurotoxic reactive astrocytes. J Neurotrauma 2018.
Kim YC, Kim YH, Kim JW, Ha KY. Transplantation of Mesenchymal Stem Cells for Acute Spinal Cord Injury in Rats: Comparative Study between Intralesional Injection and Scaffold Based Transplantation. J Korean Med Sci 2016; 31(9): 1373-82.
Uibo R, Laidmae I, Sawyer ES, et al. Soft materials to treat central nervous system injuries: evaluation of the suitability of non-mammalian fibrin gels. Biochim Biophys Acta 2009; 1793(5): 924-30.
Brown AC, Barker TH. Fibrin-based biomaterials: modulation of macroscopic properties through rational design at the molecular level. Acta Biomater 2014; 10(4): 1502-14.

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Year: 2019
Page: [52 - 62]
Pages: 11
DOI: 10.2174/1871527317666181105101756
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